chr1-237456592-C-T

Variant names:

• chr1-237456592-C-T
• rs876657575
• NM_001035.3:c.1477-8C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001035.3(RYR2):​c.1477-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,288,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002918
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.572
• Publications: 0 publications found

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-237456592-C-T is Benign according to our data. Variant chr1-237456592-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.1477-8C>T		splice_region intron	N/A	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.1477-8C>T		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1477-8C>T		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1477-8C>T		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 4 AN: 143328 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000696

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000220 AC: 4 AN: 181542 AF XY: 0.0000200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000332

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 16 AN: 1288454 Hom.: 0 Cov.: 39 AF XY: 0.0000143 AC XY: 9 AN XY: 630522

African (AFR) AF: 0.0000362 AC: 1 AN: 27608

American (AMR) AF: 0.0000740 AC: 2 AN: 27018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21148

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33822

South Asian (SAS) AF: 0.0000171 AC: 1 AN: 58488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5014

European-Non Finnish (NFE) AF: 0.0000108 AC: 11 AN: 1018248

Other (OTH) AF: 0.00 AC: 0 AN: 51920

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000279 AC: 4 AN: 143328 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 2 AN XY: 69284

African (AFR) AF: 0.0000258 AC: 1 AN: 38790

American (AMR) AF: 0.0000696 AC: 1 AN: 14372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 4706

South Asian (SAS) AF: 0.00 AC: 0 AN: 4488

European-Finnish (FIN) AF: 0.000114 AC: 1 AN: 8752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65744

Other (OTH) AF: 0.00 AC: 0 AN: 1928

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.34
DANN	Benign	0.61
PhyloP100		-0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876657575; hg19: chr1-237619892;